PROJECT SUMMARY/ABSTRACT Pathogenic variations in SCN1A, the prototypical sodium channel gene, underlie a febrile seizure phenotype ranging from mild genetic epilepsy with febrile seizures plus syndrome (GEFS+) to treatment resistant Dravet Syndrome (DS). Human and experimental research show that pathogenic variation in SCN1A is a risk factor for sudden unexpected death in epilepsy (SUDEP) in about 4% of individuals affected by DS and in unknown fraction of individuals affected by the milder GEFS+ phenotype. While the majority of SCN1A carriers escape SUDEP, it remains unclear when the SCN1A gene based variation becomes a liability for premature mortality and a correlation among SCN1A properties and SUDEP risk has never been evaluated. Experimental and human research in epilepsy and SUDEP suggests that modifier alleles may exert their effects through intragenic or oligogenic mechanism or through gene interaction networks. It is our central hypothesis that SCN1A gene based liability to SUDEP rests either in (a) an intragenic SCN1A gene based patterns of common variants with subthreshold effect co-segregating with de novo and inherited rare pathogenic variants functionally manifest in the epileptic phenotype, and/or in (b) co-occurrence of de novo and inherited rare pathogenic variants in other known SUDEP genes. In this pilot study we plan to apply novel computational methods to probe three questions, (i) is the combined effects of common and rare SCN1A gene variants sufficient and necessary to result in SUDEP in carriers of pathogenic SCN1A variants (aim 1)? (ii) is SUDEP risk modulated by co-variation in known sudden death genes (SUDEP genes) (aim2)? (iii) does co-variation in SUDEP genes affect mortality risk in patients with febrile seizure phenotype independent of SCN1A gene (aim 3)? We plan to address questions by evaluating clinical profiles and outcome data as well as exome based and copy number variants in 62 known SUDEP genes in two patient cohorts (a) in over 300 carriers of pathogenic variants in the SCN1A gene referred for whole exome clinical sequencing to the Baylor Genetic Diagnostic Laboratory (BG) (aims 1 and 2) and b) in 172 probands and 68 familial controls of the FEBrile STATus epilepticus study (FEBSTAT) cohort. The goal of this pilot project is to develop critically needed bioinformatic tools for genomic SUDEP risk stratification. The results will have an immediate impact on SUDEP risk stratification in patients with epilepsy due to SCN1A gene pathogenic variation, and they will inform future bioinformatics and statistical design when analyzing SUDEP risk in patients with the clinically very common febrile seizure phenotype as well as when evaluating causality in existing collections of SUDEP cases.